Abstract The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis has been implicated in age related diseases including prostate cancer. Humans with Laron syndrome lack functional growth hormone receptors (GHRs) and have reduced rates of cancer and diabetes. Mice with homozygous null mutations in Ghr are also protected from cancer in the C3(1)/TAg prostate cancer model. Similarly, rats lacking a functional GH gene are protected prostate cancers in the Probasin/TAg model. GHRs are expressed in multiple tissues including the liver and prostate. Activation of GHRs in the liver by GH is the main mechanism that stimulates the release of IGF-1 into circulation. Many GH actions are mediated by the subsequent actions of IGF-1 in target tissues including the prostate. Furthermore, evidence from humans indicates that elevated circulating IGF-1 confers an increased risk for the development of several cancers including prostate cancer. The expression of GHRs in the normal prostate and by prostate cancer cells suggests that local signaling by GHRs may also be important in prostate cancer cells. Recent studies demonstrating that up-regulation of local GH synthesis by prostate cancer cells is a common feature of cancer progression further supports the potential importance of local GH/GHR actions in prostate cancer. However, several important aspects of the role of GH/IGF-1 axis in prostate cancer remain uncertain. Available studies have not addressed the potential ongoing requirement for GH signaling at different stages of prostate cancer progression, the role of local GHR signaling in prostate cancer cells, or the signal transduction mechanisms downstream of GHR activation important in prostate cancer. This project will use innovative genetic approaches in mice to address these limitations of current knowledge. Previous rodent studies were also limited because they focused only on tumors driven by disruption the function of the TP53 and RB1 tumor suppressors. This project will further determine if the requirement for intact GHR signaling extends to mouse models for prostate cancers driven by activation of the PI3K/AKT pathway that is also commonly observed in human prostate cancers. Completion of these studies will be an important step toward identifying the best ways to employ pegvisomant or other agents targeting the GH/IGF-1 axis for the treatment and/or prevention of prostate cancer.